PROJECT SUMMARY The long-term goal of this research project is to identify mechanisms by which normal tissue stem cells that initially survive exposure to radiation are expanded in vivo to maintain tissue integrity. The goal of this proposal is to uncover the mechanism of mitigation observed with drugs containing sulfonylpiperazine active groups. We will investigate whether the reconstitution of the normal tissue stem cell pool seen after application of these mitigators is a direct effect on the stem cell populations in the gut and central nervous system (CNS), or mediated by providing a microenvironment permissive for stem cell expansion. Using in vitro and in vivo model systems for acute and late radiation damage we will investigate direct and indirect effects of these drugs on stem cell expansion and plasticity and uncover the underlying signaling events that lead to radiation mitigation. Specifically, we hypothesize that radiation mitigators with sulfonylpiperazine active groups, identified in the previous funding period, affect normal tissue stem cell populations in the gut and CNS directly or indirectly through G-protein-coupled receptor-mediated signaling. The systematic study of the cellular effects of compound #15 in mitigating ARS and DEARE, and uncovering the underlying mechanisms will lay ground for finding and understanding novel dual function mitigators for acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE). This will have a wide impact on the field, as it will uncover common targets on normal tissue stem cells that can be used to mitigate radiation damage on multiple organ systems simultaneously.